FIELD OF THE INVENTION
The present invention relates to certain thiophene derivatives and their use in the practice of medicine as allosteric modulators of adenosine receptors.
Adenosine (Ado) is an autocoid (or local hormone) that modulates numerous functions in the cardiovascular and other organ systems. The actions of Ado are mediated by at least four subtypes of cell surface receptors called A.sub.1, A.sub.2a, A.sub.2b, and A.sub.3. Because of the ubiquity of adenosine receptors (AdoRs) throughout the human body, their indiscriminate activation may cause undesirable side effects. Therefore, it is desirable that drugs which are administered systemically to target these receptors have some degree of organ selectivity.
The overall function of Ado appears to be the regulation of the balance between oxygen (or energy) supply and consumption (or work). Ado increases oxygen supply by causing vasodilation and decreases oxygen consumption or work by inhibiting cellular functions, e.g., slowing of heart rate. Consistent with this protective function, A.sub.1 AdoR agonists, Ado uptake blockers and Ado deaminase inhibitors have been shown to reduce cellular damage and dysfunction during hypoxia and ischemia. This protective role of Ado and A.sub.1 AdoR agonists has been shown in heart, brain, liver, and intestines. This and other potentially beneficial actions of Ado have led to increased interest in the development of Ado-related drugs targeted to ameliorate conditions such as myocardial ischemia and stroke.
However, the widespread expression of Ado receptors and the lack of sufficiently selective adenosinc agonists have been a major impediment to the successful development of direct-acting AdoR agonists to exploit the cytoprotective properties of Ado.
A number of compounds known to modulate the action of neurotransmitters, hormones and peptides bind at sites distinct from, but functionally linked to, the primary recognition site of the respective receptors. This form of interaction between two different ligands at the same receptor protein, which may result in modulation in the form of enhancement or inhibition of each other's binding and function, is referred to as allosterism. Positive (enhancement) or negative (inhibition) allosterism are important mechanisms of action of various biologically active agents. Numerous allosteric interactions have been exploited. Among the most well known of these are the allosteric interactions between the GABA receptor and benzodiazepines; the atrial natriuretic factor (ANF) receptor and amiloride; the dextromethorphan binding site and ropizine; and the muscarinic receptor and gallamine. Allosteric modulation of the actions of Ado on the A,AdoR by several 2-amino-3-benzoylthiophenes on cultured cells, cardiac and brain preparations have been reported. The specificity of these compounds for A.sub.1 AdoRs have also been demonstrated.
It would be advantageous to provide allosteric modulators of Ado as an alternative to direct-acting Ado agonists and nuclcoside uptake blockers, preferably those which can selectively modulate the response to Ado in only those organs or localized areas of a given organ in which production of Ado is increased.
It is therefore an object of the present invention to provide allosteric modulators of Ado function.
It is a further object of the present invention to provide allosteric modulators of Ado function which provide a more selective therapeutic effect than direct-acting AdoR agonists.
It is still a further object of the present invention to provide methods of administering allosteric modulators of Ado function which limit the times and locations at which significant release of Ado occurs so that systemic side effects are minimized.